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Chemical Compound Review

Zinecard     4-[(2S)-1-(3,5- dioxopiperazin-1-yl)propan...

Synonyms: Tepirone, Cardioxane, Dexrazoxane, ICRF-187, ADR-529, ...
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Disease relevance of ICRF-187

  • ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin [1].
  • For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2 [1].
  • Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy [2].
  • Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients) [3].
  • Delayed administration of dexrazoxane provides cardioprotection against anthracyclines in breast cancer or acute myeloid leukemia [4].

High impact information on ICRF-187


Chemical compound and disease context of ICRF-187


Biological context of ICRF-187


Anatomical context of ICRF-187


Associations of ICRF-187 with other chemical compounds


Gene context of ICRF-187

  • In contrast to the chelator dexrazoxane, blockade of death receptor signaling by stable overexpression of transdominant negative adapter molecule FADD did not inhibit doxorubicin-induced cell death [20].
  • To investigate Egr-1 function in the heart, we compared the molecular and histological responses of wild type (+/+) and Egr-1 deficient (-/-) female mice to saline, DOX, VP16, the cardioprotectant dexrazoxane (DZR), or DOX+DZR injection [21].
  • CONCLUSION: When combined with doxorubicin (60 mg/m2) and dexrazoxane (600 mg/m2), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m2, and G-CSF was required to prevent febrile neutropenia [22].
  • EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy [23].
  • Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy [24].

Analytical, diagnostic and therapeutic context of ICRF-187

  • Dexrazoxane and the ASCO guidelines for the use of chemotherapy and radiotherapy protectants: a critique [25].
  • Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated [26].
  • Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography [27].
  • Additional studies of anthracycline metabolism when given in combination with dexrazoxane, both in single arm and randomized cross-over studies, have generally shown no change in anthracycline metabolism, including pharmacokinetic parameters of alpha, beta, and gamma half-lives, area-under-the-curve, or clearance [28].
  • Dexrazoxane was also shown to have no effect on the event-free survival rate at 2.5 years, emphasizing that it does not detrimentally affect the efficacy of anthracycline therapy [29].


  1. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. Hochster, H., Liebes, L., Wadler, S., Oratz, R., Wernz, J.C., Meyers, M., Green, M., Blum, R.H., Speyer, J.L. J. Natl. Cancer Inst. (1992) [Pubmed]
  2. Anthracycline-induced cardiotoxicity. Shan, K., Lincoff, A.M., Young, J.B. Ann. Intern. Med. (1996) [Pubmed]
  3. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Moghrabi, A., Levy, D.E., Asselin, B., Barr, R., Clavell, L., Hurwitz, C., Samson, Y., Schorin, M., Dalton, V.K., Lipshultz, S.E., Neuberg, D.S., Gelber, R.D., Cohen, H.J., Sallan, S.E., Silverman, L.B. Blood (2007) [Pubmed]
  4. Delayed administration of dexrazoxane provides cardioprotection against anthracyclines in breast cancer or acute myeloid leukemia. Lemez, P. J. Clin. Oncol. (1997) [Pubmed]
  5. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Sawyer, D.B., Fukazawa, R., Arstall, M.A., Kelly, R.A. Circ. Res. (1999) [Pubmed]
  6. Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy. Basser, R.L., Sobol, M.M., Duggan, G., Cebon, J., Rosenthal, M.A., Mihaly, G., Green, M.D. J. Clin. Oncol. (1994) [Pubmed]
  7. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane. Bernitsas, E., Wei, W., Mikol, D.D. Ann. Neurol. (2006) [Pubmed]
  8. Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Hoekman, K., van der Vijgh, W.J., Vermorken, J.B. Drugs (1999) [Pubmed]
  9. Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Cvetković, R.S., Scott, L.J. Drugs (2005) [Pubmed]
  10. The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Hasinoff, B.B., Abram, M.E., Barnabé, N., Khélifa, T., Allan, W.P., Yalowich, J.C. Mol. Pharmacol. (2001) [Pubmed]
  11. Dexrazoxane has no impact on sensitivity of childhood leukemic blasts to daunorubicin. Styczynski, J., Wysocki, M., Balwierz, W., Kowalczyk, J.R. Leukemia (2002) [Pubmed]
  12. Mitindomide is a catalytic inhibitor of DNA topoisomerase II that acts at the bisdioxopiperazine binding site. Hasinoff, B.B., Creighton, A.M., Kozlowska, H., Thampatty, P., Allan, W.P., Yalowich, J.C. Mol. Pharmacol. (1997) [Pubmed]
  13. In vitro effects of dexrazoxane (Zinecard) and classical acute leukemia therapy: time to consider expanded clinical trials? Budman, D.R., Calabro, A., Kreis, W. Leukemia (2001) [Pubmed]
  14. Strategies for reduction of anthracycline cardiac toxicity. Speyer, J., Wasserheit, C. Semin. Oncol. (1998) [Pubmed]
  15. Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation. Ryan, T.P., Samokyszyn, V.M., Dellis, S., Aust, S.D. Chem. Res. Toxicol. (1990) [Pubmed]
  16. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. Hensley, M.L., Schuchter, L.M., Lindley, C., Meropol, N.J., Cohen, G.I., Broder, G., Gradishar, W.J., Green, D.M., Langdon, R.J., Mitchell, R.B., Negrin, R., Szatrowski, T.P., Thigpen, J.T., Von Hoff, D., Wasserman, T.H., Winer, E.P., Pfister, D.G. J. Clin. Oncol. (1999) [Pubmed]
  17. In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl)propane] onto an existing ferric-anthracycline complex. Sobol, M.M., Amiet, R.G., Green, M.D. Mol. Pharmacol. (1992) [Pubmed]
  18. Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Barnabé, N., Zastre, J.A., Venkataram, S., Hasinoff, B.B. Free Radic. Biol. Med. (2002) [Pubmed]
  19. Inhibition of anthracycline semiquinone formation by ICRF-187 (dexrazoxane) in cells. Malisza, K.L., Hasinoff, B.B. Free Radic. Biol. Med. (1996) [Pubmed]
  20. CD95/Apo-1/Fas: independent cell death induced by doxorubicin in normal cultured cardiomyocytes. Jeremias, I., Stahnke, K., Debatin, K.M. Cancer Immunol. Immunother. (2005) [Pubmed]
  21. Diminished molecular response to doxorubicin and loss of cardioprotective effect of dexrazoxane in Egr-1 deficient female mice. Saadane, N., Yue, P., Alpert, L., Mitmaker, B., Kirby, G.M., Chalifour, L.E. Can. J. Physiol. Pharmacol. (2001) [Pubmed]
  22. Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. Sparano, J.A., Speyer, J., Gradishar, W.J., Liebes, L., Sridhara, R., Mendoza, S., Fry, D., Egorin, M.J. J. Clin. Oncol. (1999) [Pubmed]
  23. Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors. Hofland, K.F., Thougaard, A.V., Dejligbjerg, M., Jensen, L.H., Kristjansen, P.E., Rengtved, P., Sehested, M., Jensen, P.B. Clin. Cancer Res. (2005) [Pubmed]
  24. Chemoprotectants: a review of their clinical pharmacology and therapeutic efficacy. Links, M., Lewis, C. Drugs (1999) [Pubmed]
  25. Dexrazoxane and the ASCO guidelines for the use of chemotherapy and radiotherapy protectants: a critique. Hellmann, K. J. Clin. Oncol. (2000) [Pubmed]
  26. Recent advances in the prevention of anthracycline cardiotoxicity in childhood. Iarussi, D., Indolfi, P., Casale, F., Coppolino, P., Tedesco, M.A., Di Tullio, M.T. Current medicinal chemistry. (2001) [Pubmed]
  27. Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. Tetef, M.L., Synold, T.W., Chow, W., Leong, L., Margolin, K., Morgan, R., Raschko, J., Shibata, S., Somlo, G., Yen, Y., Groshen, S., Johnson, K., Lenz, H.J., Gandara, D., Doroshow, J.H. Clin. Cancer Res. (2001) [Pubmed]
  28. Clinical pharmacology of dexrazoxane. Hochster, H.S. Semin. Oncol. (1998) [Pubmed]
  29. Exposure to anthracyclines during childhood causes cardiac injury. Lipshultz, S.E. Semin. Oncol. (2006) [Pubmed]
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